Spontaneous Clearance of Vertically Acquired Hepatitis C Infection: Implications for Testing and Treatment.

BACKGROUND: Current guidelines recommend that infants born to women with hepatitis C virus (HCV) viremia be screened for HCV antibody at age 18 months and, if positive, referred for RNA testing at 3 years to confirm chronic infection. This policy is based, in part, on analyses that suggest that 25%-40% of vertically acquired HCV infections clear spontaneously within 4-5 years. METHODS: Data on 179 infants with HCV RNA and/or anti-HCV evidence of vertically acquired infection in 3 prospective European cohorts were investigated. Ages at clearance of infection were estimated taking account of interval censoring and delayed entry. We also investigated clearance in initially HCV RNA-negative infants in whom RNA was not detectable until after 6 weeks. RESULTS: Clearance rates were initially high then declined slowly. Apparently, many infections clear before they can be confirmed. An estimated 65.9% (95% credible interval [CrI], 50.1-81.6) of confirmed infections cleared by 5 years, at a median 12.4 (CrI, 7.1-18.9) months. If treatment were to begin at age 6 months, 18 months, or 3 years, at least 59.0% (CrI, 42.0-76.9), 39.7% (CrI, 17.9-65.9), and 20.9% (CrI, 4.6-44.8) of those treated would clear without treatment. In 7 (6.6%) confirmed infections, RNA was not detectable until after 6 weeks and not until after 6 months in 2 (1.9%). However, all such cases subsequently cleared. CONCLUSIONS: Most confirmed infection cleared by age 3 years. Treatment before age 3, if it was available, would avoid loss to follow-up but would result in substantial overtreatment.

Overall Vertical Transmission of Hepatitis C Virus, Transmission Net of Clearance, and Timing of Transmission.

BACKGROUND: It is widely accepted that the risk of hepatitis C virus (HCV) vertical transmission (VT) is 5%-6% in monoinfected women, and that 25%-40% of HCV infection clears spontaneously within 5 years. However, there is no consensus on how VT rates should be estimated, and there is a lack of information on VT rates "net" of clearance. METHODS: We reanalyzed data on 1749 children in 3 prospective cohorts to obtain coherent estimates of overall VT rate and VT rates net of clearance at different ages. Clearance rates were used to impute the proportion of uninfected children who had been infected and then cleared before testing negative. The proportion of transmission early in utero, late in utero, and at delivery was estimated from data on the proportion of HCV RNA positive within 3 days of birth, and differences between elective cesarean and nonelective cesarean deliveries. RESULTS: Overall VT rates were 7.2% (95% credible interval [CrI], 5.6%-8.9%) in mothers who were human immunodeficiency virus (HIV) negative and 12.1% (95% CrI, 8.6%-16.8%) in HIV-coinfected women. The corresponding rates net of clearance at 5 years were 2.4% (95% CrI, 1.1%-4.1%), and 4.1% (95% CrI, 1.7%-7.3%). We estimated that 24.8% (95% CrI, 12.1%-40.8%) of infections occur early in utero, 66.0% (95% CrI, 42.5%-83.3%) later in utero, and 9.3% (95% CrI, 0.5%-30.6%) during delivery. CONCLUSIONS: Overall VT rates are about 24% higher than previously assumed, but the risk of infection persisting beyond age 5 years is about 38% lower. The results can inform design of trials of interventions to prevent or treat pediatric HCV infection, and strategies to manage children exposed in utero.

The response of the innate immune and cardiovascular systems to LPS in pregnant and nonpregnant mice.

Sepsis is the leading cause of direct maternal mortality, but there are no data directly comparing the response to sepsis in pregnant and nonpregnant (NP) individuals. This study uses a mouse model of sepsis to test the hypothesis that the cardiovascular response to sepsis is more marked during pregnancy. Female CD1 mice had radiotelemetry probes implanted and were time mated. NP and day 16 pregnant CD-1 mice received intraperitoneal lipopolysaccharide (LPS; 10 µg, serotype 0111: B4). In a separate study, tissue and serum (for RNA, protein and flow cytometry studies), aorta and uterine vessels (for wire myography) were collected after LPS or vehicle control administration. Administration of LPS resulted in a greater fall in blood pressure in pregnant mice compared to NP mice. This occurred with similar changes in the circulating levels of cytokines, vasoactive factors, and circulating leukocytes, but with a greater monocyte and lesser neutrophil margination in the lungs of pregnant mice. Baseline markers of cardiac dysfunction and apoptosis as well as cytokine expression were higher in pregnant mice, but the response to LPS was similar in both groups as was the ex vivo assessment of vascular function. In pregnant mice, nonfatal sepsis is associated with a more marked hypotensive response but not a greater immune response. We conclude that endotoxemia induces a more marked hypotensive response in pregnant compared to NP mice. These changes were not associated with a more marked systemic inflammatory response in pregnant mice, although monocyte lung margination was greater. The more marked hypotensive response to LPS may explain the greater vulnerability to some infections exhibited by pregnant women.

Tracheal CT morphology: correlation with distribution and extent of thoracic adipose tissue.

OBJECTIVE: To evaluate the relationship between adipose tissue measurements and anterior bowing of the posterior tracheal wall in a large nonselected group of patients undergoing CT pulmonary angiography (CTPA). METHODS: Consecutive patients undergoing CTPA over a 4-month period were analyzed retrospectively. Using an adapted scoring system (posterior bowing, flattening, mild/moderate or severe anterior bowing of the posterior tracheal membrane), the axial morphology and cross-sectional area of the trachea at the narrowest point and 1 cm above the aortic arch were evaluated. Measurements of adipose tissue were taken (anterior mediastinal fat width, sagittal upper abdominal diameter and subcutaneous fat thickness at the level of the costophrenic angle). Relationships between tracheal morphology and measurements of adipose tissue were analyzed. RESULTS: 296 patients were included (120 males, 176 females, mean age 59 years, range 19-90). Severe anterior bowing of the posterior tracheal wall correlated with increasing sagittal upper abdominal diameter (p = 0.002). Mild/moderate and severe anterior bowing of the posterior tracheal wall correlated with increasing mediastinal fat width (p = 0.000 and p = 0.031, respectively). Tracheal cross-sectional area was inversely correlated with increasing subcutaneous fat thickness (p = 0.022). CONCLUSION: The findings demonstrate a statistically significant relationship between CT tracheal morphology and adipose tissue measurements in a large nonselected population. KEY POINTS: • There is increasing interest in the effects of obesity on the airways. • A relationship between anterior bowing of the posterior tracheal wall and adipose tissue measurements is demonstrated. • This is of clinical relevance in an increasingly obese population. • Further studies with functional correlation are required.

Salvage assessment with cardiac MRI following acute myocardial infarction underestimates potential for recovery of systolic strain.

OBJECTIVES: Our aim was to evaluate the relationship between the degree of salvage following acute ST elevation myocardial infarction (STEMI) and subsequent reversible contractile dysfunction using cardiac magnetic resonance (CMR) imaging. METHODS: Thirty-four patients underwent CMR examination 1-7 days after primary percutaneous coronary intervention (PPCI) for acute STEMI with follow-up at 1 year. The ischaemic area-at-risk (AAR) was assessed with T2-weighted imaging and myocardial necrosis with late gadolinium enhancement. Myocardial strain was quantified with complementary spatial modulation of magnetisation (CSPAMM) tagging. RESULTS: Ischaemic segments with poor (<25 %) or intermediate (26-50 %) salvage index were associated with worse Eulerian circumferential (Ecc) strain immediately post-PPCI (-9.1 % ± 0.6, P = 0.033 and -11.8 % ± 1.3, P = 0.003, respectively) than those with a high (51-100 %) salvage index (-14.4 % ± 1.3). Mean strain in ischaemic myocardium improved between baseline and follow-up (-10.1 % ± 0.5 vs. -16.2 % ± 0.5 %, P < 0.0001). Segments with poor salvage also showed an improvement in strain by 1 year (-9.1 % ± 0.6 vs. -15.3 % ± 0.6, P = 0.033) although they remained the most functionally impaired. CONCLUSIONS: Partial recovery of peak systolic strain following PPCI is observed even when apparent salvage is less than 25 %. Late gadolinium enhancement (LGE) may not equate to irreversibly injured myocardium and salvage assessment performed within the first week of revascularisation may underestimate the potential for functional recovery. KEY POINTS: • MRI can measure how much myocardium is damaged after a heart attack. • Heart muscle that appears initially non-viable may sometimes partially recover. • Enhancement around the edges of infarcts may resolve over time. • Evaluating new cardio-protective treatments with MRI requires appreciation of its limitations.

Impact of screening for risk of suicide: randomised controlled trial.

BACKGROUND: Concerns have been expressed about the impact that screening for risk of suicide may have on a person's mental health. AIMS: To examine whether screening for suicidal ideation among people who attend primary care services and have signs of depression increases the short-term incidence of feeling that life is not worth living. METHOD: In a multicentre, single-blind, randomised controlled trial, 443 patients in four general practices were randomised to screening for suicidal ideation or control questions on health and lifestyle (trial registration: ISRCTN84692657). The primary outcome was thinking that life is not worth living measured 10-14 days after randomisation. Secondary outcome measures comprised other aspects of suicidal ideation and behaviour. RESULTS: A total of 443 participants were randomised to early (n = 230) or delayed screening (n = 213). Their mean age was 48.5 years (s.d. = 18.4, range 16-92) and 137 (30.9%) were male. The adjusted odds of experiencing thoughts that life was not worth living at follow-up among those randomised to early compared with delayed screening was 0.88 (95% CI 0.66-1.18). Differences in secondary outcomes between the two groups were not seen. Among those randomised to early screening, 37 people (22.3%) reported thinking about taking their life at baseline and 24 (14.6%) that they had this thought 2 weeks later. CONCLUSIONS: Screening for suicidal ideation in primary care among people who have signs of depression does not appear to induce feelings that life is not worth living.

Insufficient acetabular version increases blood metal ion levels after metal-on-metal hip resurfacing.

BACKGROUND: Many factors affect the blood metal ion levels after metal-on-metal (MOM) hip arthroplasty. The main surgically adjustable variable is the amount of coverage of the head provided by the cup which is a function of the inclination and version angles. However, most studies have used plain radiographs which have questionable precision and accuracy, particularly for version and large diameter metal heads; further, these studies do not simultaneously assess version and inclination. Thus the relationship between version and blood metal ions levels has not been resolved. QUESTIONS/PURPOSES: We determined whether cup inclination and version influence blood metal ion levels while adjusting for age at assessment, gender, body mass index, horizontal femoral offset, head size, manufacturer hip type, and Oxford hip score. PATIENTS AND METHODS: We prospectively followed 100 individuals (51 females, 49 males) with unilateral MOM hip resurfacing who underwent clinical assessment, CT scanning, and blood metal ion measurement. Multiple regression analysis was used to determine which variables were predictors of blood metal ion levels and to model the effect of these variables. RESULTS: Only cup inclination, version angles, and gender influenced blood cobalt or chromium levels. Cobalt and chromium levels positively correlated with inclination angle and negatively correlated with version angle. The effect of changes in version angle was less than for inclination angle. Based on our observations, we developed a formula to predict the effect of these parameters on metal ion levels. CONCLUSIONS: Our data suggest insufficient cup version can cause high blood metal ions after MOM hip arthroplasty. We were unable to show that excessive version caused high levels. LEVEL OF EVIDENCE: Level II, prognostic study. See Guidelines for Authors for a complete description of levels of evidence.

Factors associated with shorter length of admission among people with dementia in England and Wales: retrospective cohort study.

OBJECTIVES: To identify aspects of the organisation and delivery of acute inpatient services for people with dementia that are associated with shorter length of hospital stay. DESIGN AND SETTING: Retrospective cohort study of patients admitted to 200 general hospitals in England and Wales. PARTICIPANTS: 10 106 people with dementia who took part in the third round of National Audit of Dementia. MAIN OUTCOME MEASURE: Length of admission to hospital. RESULTS: The median length of stay was 12 days (IQR=6-23 days). People with dementia spent less time in hospital when discharge planning was initiated within 24 hours of admission (estimated effect -0.24, 95% CI: -0.29 to -0.18, p<0.001). People from ethnic minorities had shorter length of stay (difference -0.066, 95% CI: -0.13 to -0.002, p=0.043). Patients with documented evidence of discussions having taken place between their carers and medical staff spent longer in hospital (difference 0.26, 95% CI: 0.21 to 0.32, p<0.001). These associations held true in a subsample of 669 patients admitted with hip fracture and data from 74 hospitals with above average carer-rated quality of care. CONCLUSIONS: The way that services for inpatients with dementia are delivered can influence how long they spend in hospital. Initiating discharge planning within the first 24 hours of admission may help reduce the amount of time that people with dementia spend in hospital.

Broadening Options for Long-term Dialysis in the Elderly (BOLDE): differences in quality of life on peritoneal dialysis compared to haemodialysis for older patients.

BACKGROUND: Health-related quality of life (QOL) is an important outcome for older people who are often on dialysis for life. Little is, however, known about differences in QOL on haemodialysis (HD) and peritoneal dialysis (PD) in older age groups. Randomising patients to either modality to assess outcomes is not feasible. METHODS: In this cross-sectional, multi-centred study we conducted QOL assessments (Short Form-12 Mental and Physical Component Summary scales, Hospital Anxiety and Depression Scale and Illness Intrusiveness Ratings Scale) in 140 people (aged 65 years or older) on PD and HD. RESULTS: The groups were similar in age, gender, time on dialysis, ethnicity, Index of Deprivation (based on postcode), dialysis adequacy, cognitive function (Mini-Mental State Exam and Trail-Making Test B), nutritional status (Subjective Global Assessment) and social networks. There was a higher comorbidity score in the HD group. Regression analyses were undertaken to ascertain which variables significantly influence each QOL assessment. All were influenced by symptom count highlighting that the patient's perception of their symptoms is a critical determinant of their mental and physical well being. Modality was found to be an independent predictor of illness intrusion with greater intrusion felt in those on HD. CONCLUSIONS: Overall, in two closely matched demographic groups of older dialysis patients, QOL was similar, if not better, in those on PD. This study strongly supports offering PD to all suitable older people.

Live lecture versus video podcast in undergraduate medical education: A randomised controlled trial.

BACKGROUND: Information technology is finding an increasing role in the training of medical students. We compared information recall and student experience and preference after live lectures and video podcasts in undergraduate medical education. METHODS: We performed a crossover randomised controlled trial. 100 students were randomised to live lecture or video podcast for one clinical topic. Live lectures were given by the same instructor as the narrator of the video podcasts. The video podcasts comprised Powerpoint™ slides narrated using the same script as the lecture. They were then switched to the other group for a second clinical topic. Knowledge was assessed using multiple choice questions and qualitative information was collected using a questionnaire. RESULTS: No significant difference was found on multiple choice questioning immediately after the session. The subjects enjoyed the convenience of the video podcast and the ability to stop, review and repeat it, but found it less engaging as a teaching method. They expressed a clear preference for the live lecture format. CONCLUSIONS: We suggest that video podcasts are not ready to replace traditional teaching methods, but may have an important role in reinforcing learning and aiding revision.

Longitudinal Trends in Quality of Life and Physical Function in Frail Older Dialysis Patients: A Comparison of Assisted Peritoneal Dialysis and In-Center Hemodialysis.

BACKGROUND: In-center hemodialysis (HD) has been the standard treatment for older dialysis patients, but reports suggest an associated decline in physical and cognitive function. Cross-sectional data suggest that assisted peritoneal dialysis (aPD), an alternative treatment, is associated with quality of life (QoL) outcomes that are comparable to in-center HD. We compared longitudinal changes in QoL between modalities. METHODS: We enrolled 106 aPD patients, matched with 100 HD patients from 20 renal centers in England and Northern Ireland. Patients were assessed quarterly for 2 years using the Hospital Anxiety and Depression Scale (HADS), SF-12 physical and mental scores, symptom score, Illness Intrusiveness Rating Scale (IIRS), Barthel's score, and the Renal Treatment Satisfaction Questionnaire (RTSQ). Mixed model analysis was used to assess the impact of dialysis modality on these outcomes during follow-up. P values were adjusted for multiple significance testing. RESULTS: Multivariate analysis showed no difference in any of the outcome measures between aPD and HD. Longitudinal trends in outcomes were also not significantly different. Higher age at baseline was associated with lower IIRS and RTSQ scores during follow-up. One-hundred and twenty-five (60.6%) patients dropped out of the study: 59 (28.6%) died, 61 (29.6%) withdrew during follow-up, and 5 (2.5%) were transplanted. CONCLUSIONS: Quality of life outcomes in frail older aPD patients were equivalent to those receiving in-center HD. Assisted PD is thus a valid alternative to HD for older people with end-stage kidney disease (ESKD) wishing to dialyze at home.

Psychiatric adjustment in the year after meningococcal disease in childhood.

OBJECTIVE: To assess psychiatric status after meningococcal disease. METHOD: Cohort study of 66 children (34 boys, 32 girls) ages 4 to 17 years admitted to pediatric hospitals with meningococcal disease. The main outcome measure was psychiatric disorder (1-year period and point prevalence on the Schedule for Affective Disorders and Schizophrenia for School-Age Children interview for children 6 years or older; point prevalence in younger children on the Behavior Screening Questionnaire). RESULTS: During the course of the year after discharge from hospital, psychiatric disorders were identified in 23 of 40 (57%) children ages 6 years or older. The most common primary disorders were depressive, oppositional defiant, and anxiety disorders. At the time of 12-month follow-up, psychiatric disorders were present in 13 of 40 (32%) of those ages 6 or older and in 7 of 26 (26%) under 6 years old. Two children had a diagnosis of posttraumatic stress disorder. Logistic regression analysis showed that global meningococcal illness severity score, clinical shock on admission, and impairing premorbid emotional and behavioral problems in the child were independent predictors of psychiatric disorder at 12-month follow-up. CONCLUSIONS: Psychiatric disorders are common in the year after meningococcal disease. Especially at risk are children who are severely medically ill and those with more impairing premorbid emotional and behavioral problems.

Hierarchical statistical techniques are necessary to draw reliable conclusions from analysis of isolated cardiomyocyte studies.

AIMS: It is generally accepted that post-MI heart failure (HF) changes a variety of aspects of sarcoplasmic reticular Ca2+ fluxes but for some aspects there is disagreement over whether there is an increase or decrease. The commonest statistical approach is to treat data collected from each cell as independent, even though they are really clustered with multiple likely similar cells from each heart. In this study, we test whether this statistical assumption of independence can lead the investigator to draw conclusions that would be considered erroneous if the analysis handled clustering with specific statistical techniques (hierarchical tests). METHODS AND RESULTS: Ca2+ transients were recorded in cells loaded with Fura-2AM and sparks were recorded in cells loaded with Fluo-4AM. Data were analysed twice, once with the common statistical approach (assumption of independence) and once with hierarchical statistical methodologies designed to allow for any clustering. The statistical tests found that there was significant hierarchical clustering. This caused the common statistical approach to underestimate the standard error and report artificially small P values. For example, this would have led to the erroneous conclusion that time to 50% peak transient amplitude was significantly prolonged in HF. Spark analysis showed clustering, both within each cell and also within each rat, for morphological variables. This means that a three-level hierarchical model is sometimes required for such measures. Standard statistical methodologies, if used instead, erroneously suggest that spark amplitude is significantly greater in HF and spark duration is reduced in HF. CONCLUSION: Ca2+ fluxes in isolated cardiomyocytes show so much clustering that the common statistical approach that assumes independence of each data point will frequently give the false appearance of statistically significant changes. Hierarchical statistical methodologies need a little more effort, but are necessary for reliable conclusions. We present cost-free simple tools for performing these analyses.

Erratum: High speed sCMOS-based oblique plane microscopy applied to the study of calcium dynamics in cardiac myocytes: [J. Biophotonics 9, No. 3, 311-323 (2016)].

In the article by M.B. Sikkel et al. (doi: 10.1002/jbio.201500193), published in J. Biophotonics 9, 311-323 (2016), an error occurred in the computer code that was used to generate Figure 3. This erratum is published to correct Figure 3, the calculated value of tgeom and the experimentally determined value of toptics in the text of the article.

Improving GHB withdrawal with baclofen: study protocol for a feasibility study for a randomised controlled trial.

BACKGROUND: GHB (gamma-hydroxybutyrate) and its pro-drugs GBL (gamma-butyrolactone) and 1,4-butanediol (1,4-BD) are central nervous system depressants whose street names include 'G' and 'liquid ecstasy'. They are used recreationally predominately for their stimulant and pro-sexual effects or for sedation to help with sleep and/or to 'come down' after using stimulant recreational drugs. Although overall population prevalence is low (0.1 %), in some groups such as men who have sex with men, GHB/GBL use may reach 20 %. GHB/GBL dependence may be associated with severe withdrawal with individuals presenting either acutely to emergency departments or to addiction services for support. Benzodiazepines are currently prescribed for GHB/GBL detoxification but do not prevent all complications, such as behavioural disinhibition, that may require hospitalisation or admission to a high dependency/intensive care unit. The GABAB receptor mediates most effects of GHB/GBL and the GABAB agonist, baclofen, has shown promise as an adjunct to benzodiazepines in reducing withdrawal severity when prescribed both during withdrawal and as a 2-day 'preload' prior to detoxification. The key aim of this feasibility study is provide information about recruitment and characteristics of the proposed outcome measure (symptom severity, complications including delirium and treatment escalation) to inform an application for a definitive randomised placebo controlled trial to determine the role of baclofen in the management of GHB/GBL withdrawal and whether starting baclofen 2 days earlier improves outcomes further. METHODS/DESIGN: This is a prospective, randomised, double-blind, placebo-controlled feasibility study that will recruit participants (aged over 18 years) who are GHB/GBL-dependent and wish to undergo planned GHB/GBL detoxification or are at risk of acute withdrawal and are inpatients requiring unplanned withdrawal. We aim to recruit 88 participants: 28 unplanned inpatients and 60 planned outpatients. During detoxification we will compare baclofen 10 mg three times a day with placebo as an adjunct to the usual benzodiazepine regimen. In the planned outpatient arm, we will also compare a 2-day preload of baclofen 10 mg three times a day with placebo. Ratings of GHB/GBL withdrawal, sleep, depression, anxiety as well as GHB/GBL use will be collected. The main data analyses will be descriptive about recruitment and characterising the impact of adding baclofen to the usual benzodiazepine regimen on measures and outcomes of GHB/GBL withdrawal to provide estimates of variability and effect size. A qualitative approach will evaluate research participant and clinician acceptability and data collected to inform cost-effectiveness. DISCUSSION: This feasibility study will inform a randomised controlled trial to establish whether adding baclofen to a benzodiazepine regimen reduces the severity and complications of GHB/GBL withdrawal. TRIAL REGISTRATION: ISRCTN59911189 . Registered 14 October 2015. PROTOCOL: v3.1, 1 February 2016.

High speed sCMOS-based oblique plane microscopy applied to the study of calcium dynamics in cardiac myocytes.

Oblique plane microscopy (OPM) is a form of light sheet microscopy that uses a single high numerical aperture microscope objective for both fluorescence excitation and collection. In this paper, measurements of the relative collection efficiency of OPM are presented. An OPM system incorporating two sCMOS cameras is then introduced that enables single isolated cardiac myocytes to be studied continuously for 22 seconds in two dimensions at 667 frames per second with 960 × 200 pixels and for 30 seconds with 960 × 200 × 20 voxels at 25 volumes per second. In both cases OPM is able to record in two spectral channels, enabling intracellular calcium to be studied via the probe Fluo-4 AM simultaneously with the sarcolemma and transverse tubule network via the membrane dye Cellmask Orange. The OPM system was then applied to determine the spatial origin of spontaneous calcium waves for the first time and to measure the cell transverse tubule structure at their point of origin. Further results are presented to demonstrate that the OPM system can also be used to study calcium spark parameters depending on their relationship to the transverse tubule structure.

Adverse remodeling of the electrophysiological response to ischemia-reperfusion in human heart failure is associated with remodeling of metabolic gene expression.

BACKGROUND: Ventricular arrhythmias occur more frequently in heart failure during episodes of ischemia-reperfusion although the mechanisms underlying this in humans are unclear. We assessed, in explanted human hearts, the remodeled electrophysiological response to acute ischemia-reperfusion in heart failure and its potential causes, including the remodeling of metabolic gene expression. METHODS AND RESULTS: We optically mapped coronary-perfused left ventricular wedge preparations from 6 human end-stage failing hearts (F) and 6 donor hearts rejected for transplantation (D). Preparations were subjected to 30 minutes of global ischemia, followed by 30 minutes of reperfusion. Failing hearts had exaggerated electrophysiological responses to ischemia-reperfusion, with greater action potential duration shortening (P<0.001 at 8-minute ischemia; P=0.001 at 12-minute ischemia) and greater conduction slowing during ischemia, delayed recovery of electric excitability after reperfusion (F, 4.8±1.8 versus D, 1.0±0 minutes; P<0.05), and incomplete restoration of action potential duration and conduction velocity early after reperfusion. Expression of 46 metabolic genes was probed using custom-designed TaqMan arrays, using extracted RNA from 15 failing and 9 donor hearts. Ten genes important in cardiac metabolism were downregulated in heart failure, with SLC27A4 and KCNJ11 significantly downregulated at a false discovery rate of 0%. CONCLUSIONS: We demonstrate, for the first time in human hearts, that the electrophysiological response to ischemia-reperfusion in heart failure is accelerated during ischemia with slower recovery after reperfusion. This can enhance spatial conduction and repolarization gradients across the ischemic border and increase arrhythmia susceptibility. This adverse response was associated with downregulation of expression of cardiac metabolic genes.